Accuracy study of Angiotensin 1-7 composite index test to predict pulmonary fibrosis and guide treatment.

BACKGROUND: Pulmonary fibrosis can develop after acute respiratory distress syndrome (ARDS). The hypothesis is we are able to measure phenotypes that lie at the origin of ARDS severity and fibrosis development. The aim is an accuracy study of prognostic circulating biomarkers. METHODS: A longitudinal study followed COVID-related ARDS patients with medical imaging, pulmonary function tests and biomarker analysis, generating 444 laboratory data. Comparison to controls used non-parametrical statistics; p < 0·05 was considered significant. Cut-offs were obtained through receiver operating curve. Contingency tables revealed predictive values. Odds ratio was calculated through logistic regression. RESULTS: Angiotensin 1-7 beneath 138 pg/mL defined Angiotensin imbalance phenotype. Hyper-inflammatory phenotype showed a composite index test above 34, based on high Angiotensin 1-7, C-Reactive Protein, Ferritin and Transforming Growth Factor-ß. Analytical study showed conformity to predefined goals. Clinical performance gave a positive predictive value of 95 % (95 % confidence interval, 82 %-99 %), and a negative predictive value of 100 % (95 % confidence interval, 65 %-100 %). Those severe ARDS phenotypes represented 34 (Odds 95 % confidence interval, 3-355) times higher risk for pulmonary fibrosis development (p < 0·001). CONCLUSIONS: Angiotensin 1-7 composite index is an early and objective predictor of ARDS evolving to pulmonary fibrosis. It may guide therapeutic decisions in targeted phenotypes.

Efficacy of Rituximab Versus Cyclophosphamide and Mycophenolate for the Treatment of Interstitial Lung Disease in Systemic Sclerosis: A Systematic Review.

Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc), contributing to significant morbidity and mortality in affected individuals. The optimal treatment approach for SSc-associated ILD remains uncertain, with rituximab, cyclophosphamide, and mycophenolate among potential therapeutic options. This systematic review aims to evaluate and synthesize the existing evidence on the efficacy of rituximab compared to cyclophosphamide and mycophenolate for the treatment of ILD in patients with systemic sclerosis. A comprehensive search of the following electronic databases, PubMed, Science Direct, Google Scholar, and Cochrane Library, has been conducted to identify relevant studies, including randomized controlled trials, systematic review and meta-analysis, prospective cohort studies, and retrospective cohort studies. Data on study characteristics, participant demographics, interventions, outcomes, and key findings have been extracted and synthesized. The risk of bias in the included studies has been assessed using appropriate tools such as the Cochrane Bias assessment tool for randomized controlled trials, the New Castle Ottawa tool for cohort studies, and the AMSTAR checklist for systematic reviews and meta-analysis. The research team ultimately selected 15 high-quality studies for review. Rituximab demonstrated similar efficacy to cyclophosphamide and mycophenolate in improving lung function (forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO)), with fewer severe adverse events. Cyclophosphamide, while effective, had higher toxicity, leading to more frequent adverse events such as leukopenia and infections. Mycophenolate showed comparable efficacy to cyclophosphamide but with fewer side effects, making it a well-tolerated alternative. The findings of this systematic review will provide valuable insights into the comparative efficacy of rituximab, cyclophosphamide, and mycophenolate in the management of ILD in systemic sclerosis, informing clinical decision-making and guiding future research in this area.

[Highlights 57th SEPAR Congress]. / Highlights del 57.° Congreso de la Sociedad Española de Neumología y Cirugía Torácica (SEPAR).

The Spanish Society of Pneumology and Thoracic Surgery (SEPAR) has held its 57th Congress in Valencia from 6 to 8 of June 2024. The SEPAR Congress is the leading meeting for the entire respiratory scientific community, which allows learning about the main scientific advances in this area and provides the ideal situation to create and strengthen ties. This year, under the title "Respiratory Health for everybody", the SEPAR Congress stressed the importance of raising awareness about the importance of caring for and protecting our respiratory system. In this review, we offer a summary of some notable issues addressed in six selected areas of interest: chronic obstructive pulmonary disease (COPD), asthma, interstitial lung diseases (ILDs), pulmonary vascular diseases, sleep and breathing disorders and respiratory physiotherapy.

Synovial fluid does not retard fluid exudation during stress-relaxation of immature bovine cartilage.

Interstitial fluid load support (FLS) is a dominant mechanism of lubrication in cartilage, producing a low friction coefficient while enhancing the tissue's load bearing capabilities. Due to its viscosity, synovial fluid (SF) may retard loss of FLS by slowing the exudation of interstitial fluid from the cartilage. This study tested this hypothesis by comparing the stress-relaxation (SRL) response of immature bovine articular cartilage immersed either in phosphate buffered saline (PBS) or in healthy mature bovine SF, under unconfined compression (fluid exudation across cut lateral tissue boundary) and indentation testing (fluid exudation across articular surface). To investigate the influence of diffusion of SF molecular constituents into cartilage, the effect of incubation time in SF on SRL was also investigated. The SRL response in unconfined compression was not significantly different in PBS versus SF when compared directly (p = 0.98) and had a slope ofm = 1.00 ± 0.04 (R2 = 0.989 ± 0.007). Samples tested in PBS exhibited characteristic relaxation times, τPBS=42.6 ± 5.3 s andτSF = 40.8 ± 4.7 s, that were not significantly different (p = 0.40). Incubation time of 24 h in SF resulted in no significant difference in the SRL response (p = 0.39, m=1.03 ± 0.12; R2=0.983 ± 0.011, andτPBS = 43.4 ± 10.7 s versusτSF = 41.5 ± 4.8 s, p = 0.59). Indentation testing showed some statistically significant, but functionally insignificant, difference in SRL responses in PBS versus SF with a slope ofm = 0.958 ± 0.060 (R2 = 0.957 ± 0.020, p = 0.029, andτPBS = 16.9 ± 2.6 s versusτSF = 19.4 ± 3.3 s, p = 0.073). Based on these results, we reject the hypothesis that healthy SF can retard the loss of FLS in cartilage due to its viscosity.

Stroke in a Patient With Pulmonary Siderosis: An Unusual Association.

Occupational lung diseases are a major hazard, which can lead to severe complications and a worsening quality of life. Out of these diseases, pulmonary siderosis was considered an innocuous disease. We detail the case of a 42-year-old man who had a history of chronic exposure to ferrous fumes due to his occupation. He presented with breathlessness and symptoms of a stroke. CT imaging studies showed an ischemic infarct in the brain and changes suggestive of interstitial lung disease in the chest, which was eventually diagnosed as pulmonary siderosis. In spite of having no comorbidities and significant past history, the patient developed a debilitating condition most likely as a consequence of the underlying lung pathology. We want to highlight the importance of early detection and proper management of interstitial lung diseases.

Efficacy and safety of oral versus intravenous cyclophosphamide in treatment of connective tissue disease-related interstitial lung disease.

OBJECTIVE: Interstitial lung disease (ILD) resulting from connective tissue disease (CTD) greatly undermines people's health. Cyclophosphamide (CYC) is a widely used agent in treating CTD-ILD. We compared the efficacy and safety of oral and intravenous CYC in CTD-ILD treatment. METHODS: The retrospectively enrolled CTD-ILD patients were divided into the oral and intravenous CYC groups. The chest high-resolution computed tomography examination, forced vital capacity (FVC), lung carbon monoxide diffusion capacity (Dlco) determinations, and 6 min walk test (6MWT) were performed pre-treatment and at the 3rd, 6th, and 12th months posttreatment. Radiographic ILD severity was assessed using the Warrick score. Krebs Von den Lungen-6, surfactant protein A (SP-A), SP-D, and erythrocyte sedimentation rate (ESR) before and at the 12th month post-treatment were determined. CYC cumulative dose and occurrence of adverse reactions during treatment were recorded. RESULTS: CYC cumulative dose in the intravenous CYC group was reduced. Compared with oral CYC treatment, intravenous CYC caused decreased Warrick score and increased FVC and 6MWT at the 6th month, and elevated DLco at the 3rd and 6th months posttreatment. SP-A, SP-D and ESR levels in both groups were reduced 12 months posttreatment, with a more evident decrease in the intravenous CYC group. Intravenous CYC had lower total adverse reaction incidence. CONCLUSION: Compared with oral CYC, intravenous CYC decreases Warrick score and increases FVC and 6MWT at 6 months posttreatment, and reduces SP-A, SP-D, and ESR levels after 12 months of treatment, which shows low CYC cumulative dose and adverse reaction incidence in treating CTD-ILD.

Pressure loading regulates the stemness of liver cancer stem cells via YAP/BMF signaling axis.

Cancer stem cells (CSCs) are considered the major cause of the occurrence, progression, chemoresistance/radioresistance, recurrence, and metastasis of cancer. Increased interstitial fluid pressure (IFP) is a key feature of solid tumors. Our previous study showed that the distribution of liver cancer stem cells (LCSCs) correlated with the mechanical heterogeneity within liver cancer tissues. However, the regulation of liver cancer's mechanical microenvironment on the LCSC stemness is not fully understood. Here, we employed a cellular pressure-loading device to investigate the effects of normal IFP (5 mmHg), as well as increased IFP (40 and 200 mmHg) on the stemness of LCSCs. Compared to the control LCSCs (exposure to 5 mmHg pressure loading), the LCSCs exposed to 40 mmHg pressure loading exhibited significantly upregulated expression of CSC markers (CD44, EpCAM, Nanog), enhanced sphere and colony formation capacities, and tumorigenic potential, whereas continuously increased pressure to 200 mmHg suppressed the LCSC characteristics. Mechanistically, pressure loading regulated Yes-associated protein (YAP) activity and Bcl-2 modifying factor (BMF) expression. YAP transcriptionally regulated BMF expression to affect the stemness of LCSCs. Knockdown of YAP and overexpression of BMF attenuated pressure-mediated stemness and tumorgenicity, while YAP-deficient and BMF-deletion recused pressure-dependent stemness on LCSCs, suggesting the involvement of YAP/BMF signaling axis in this process. Together, our findings provide a potential target for overcoming the stemness of CSCs and elucidate the significance of increased IFP in cancer progression.

APRIL/BAFF upregulation is associated with clonal B-cell expansion in Hunner-type interstitial cystitis.

Hunner-type interstitial cystitis (HIC) is a chronic inflammatory disease of the urinary bladder with an unknown etiology. We conducted comprehensive immunogenomic profiling of bladder specimens obtained by biopsy and cystectomy from 37 patients with HIC. Next-generation RNA sequencing demonstrated abundant plasma cell infiltration with frequent light chain restriction in HIC-affected bladder tissue. Subsequent analysis of the B-cell receptor repertoire revealed spatial and temporal expansion of B-cell clones. The extent of B-cell clonal expansion was significantly correlated with the gene expression levels of TNFSF13 and TNFSF13B, which encode APRIL and BAFF, respectively. These findings indicate that APRIL and BAFF are the key regulators of clonal B-cell expansion in HIC and might serve as therapeutic targets in this debilitating disease. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Regional diversity in drug-induced lung diseases among the USA, European Union, and Japan.

Background: Drug-induced lung disease (DILD) is a considerable and potentially fatal adverse event with poorly understood risk factors. Large-scale, data-driven analyses investigating regional discrepancies in DILD incidence are lacking. The aim of this study was to investigate the potential association among DILD prevalence, regional differences and other factors based on large-scale data base. Methods: This retrospective observational study analyzed spontaneous adverse event reports from the FDA Adverse Event Reporting System (FAERS) database between January 2010 and December 2020. Regional disparities in DILD incidence were assessed among reports from the United States of America (USA), the European Union (EU), and Japan (JP). Using multivariate logistic regression accounting for age, sex, and reporting years, we calculated the reporting odds ratios (RORs) with 95% confidence intervals. Subgroup analyses were performed for different types of anticancer agents, including tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs), antibody-drug conjugates (ADCs), and cytotoxic agents. Results: Regional differences in RORs were observed for anticancer drugs in reports from JP and the EU compared with those from the USA (JP, ROR 4.432; EU, ROR 1.291) and for non-anticancer drugs (JP, ROR 3.481; EU, ROR 1.086). Significantly higher RORs were observed for all anticancer drug regimens reported in JP than in the USA (TKIs, ROR 3.274; ICIs, ROR 2.170; ADCs, ROR 2.335; cytotoxic agents, ROR 3.989). The EU reports exhibited higher RORs for TKIs and cytotoxic agents than the USA reports, with no significant differences in ICIs or ADCs (TKIs, ROR 1.679; ICIs, ROR 1.041; ADCs, ROR 1.046; cytotoxic agents, ROR 1.418). Conclusion: The prevalence of DILD in JP, the EU, and the USA differed. These findings have important implications in evaluating the safety profiles of drugs and patient safety in drug development and clinical practice. This study is the first to identify regional differences in DILDs using a large global database.

Necrotizing Fasciitis Mimicking Interstitial Cystitis: An Atypical Clinical Presentation.

Necrotizing fasciitis is a severe, life-threatening disease with a nonspecific clinical presentation, making it a challenging diagnosis. Early treatment with broad-spectrum antibiotics and surgical debridement is crucial to prevent rapid disease progression and poor outcomes. Given its high mortality rate and ambiguous presentation, maintaining a high index of suspicion for necrotizing fasciitis is essential. In this case, a 60-year-old woman presented to her gynecologist with urinary tract infection symptoms of frequency, hematuria, and suprapubic pain, with a year-long history of night sweats, hematuria, dysuria, and incomplete voiding. Although initially treated with outpatient antibiotics, she returned to the emergency department one day later with severe lower abdominal pain, overlying erythema, and a high fever. Abdominal imaging revealed extensive cellulitis. Upon the development of rapidly expanding erythema and crepitus, there was concern for necrotizing fasciitis. The patient received immediate treatment with broad-spectrum antibiotics and underwent urgent surgical debridement. While she showed clinical improvement in the following days, laboratory studies revealed profound hypercalcemia, anemia, and persistent leukocytosis. Additional testing ultimately led to the diagnosis of advanced bladder cancer. This case underscores the importance of prompt recognition and treatment of necrotizing fasciitis. It also highlights the influence of confirmation and availability biases, which can lead to overlooking symptoms that may indicate more serious underlying conditions. As medical professionals, it is crucial to remain vigilant and not disregard seemingly insignificant symptoms, as they could be indicative of life-threatening diagnoses.

Anti MDA-5 associated rapidly progressive interstitial lung disease complicated by viral pneumonia - a fatal outcome.

Dermatomyositis is a heterogeneous systemic disease, with 7% to 10% of the individuals presenting the Anti MDA-5 antibody. This subset of patients has clinically amyotropic dermatomyositis, presenting with cutaneous ulcer and rapidly progressive interstitial lung disease. We report the case of a 22-year-old male with a six-month history of low-grade fever associated with myalgia, polyarthralgia, and marked weight loss. He had a history of shortness of breath and high-grade fever 15 days before admission. His clinical features and imaging workup were consistent with acute respiratory distress syndrome. A nasal swab was positive for H1N1 influenza virus infection. During the disease investigation, he succumbed after nine days of admission. The autopsy examination showed diffuse alveolar damage on a background of non-specific interstitial pattern of injury in the lungs. His postmortem muscle biopsy revealed subtle changes of inflammatory myopathy. The brain showed diffuse subarachnoid hemorrhage. Evaluation of postmortem serum sample revealed positivity for Anti MDA-5 and Ro-52 antibodies. This was a case of Anti MDA-5 and Ro-52 associated dermatomyositis with non-specific interstitial pneumonia pattern of lung injury complicated with H1N1 influenza pneumonia, leading to diffuse alveolar damage and subsequent respiratory failure and death. Serum Anti MDA-5 antibodies represent an important biomarker for diagnosing and predicting prognosis for patients with idiopathic inflammatory myopathies, especially clinically amyopathic dermatomyositis. Anti-Ro-52 has been reported in a wide variety of autoimmune diseases, particularly in myositis, scleroderma, and autoimmune liver diseases. Ro-52 autoantibodies are associated with interstitial lung disease (ILD), and their presence should encourage the clinician's curiosity to search for ILD.

Doppler ultrasound imaging and shear wave elastography for evaluation of interstitial fibrosis/tubular atrophy in IgA nephropathy.

PURPOSE: The purpose of this study was to explore the value of Doppler ultrasound imaging and shear wave elastography (SWE) in evaluating renal interstitial fibrosis/tubular atrophy (IFTA). METHODS: During April 2019 and November 2023, biopsy-proven IgA nephropathy (IgAN) patients were enrolled in our study. Conventional ultrasound, Doppler ultrasound imaging and SWE measurements were performed, and related parameters were collected. According to the Oxford classification of IgAN, interstitial fibrosis/tubular atrophy (T) lesions were grouped into T0, T1 and T2 group. Receiver operating characteristic (ROC) curves were constructed to evaluate the diagnostic accuracy of SWE in identifying IFTA. RESULTS: A total of 100 IgAN patients were enrolled in the final cohort. 67 patients were in the T0 group, and 33 patients were in the T1/T2 group. The average SWE values were 42.17 ± 9.11 kPa in the T0 group and 36.83 ± 10.32 kPa in the T1/T2 group (p = 0.01). Multivariate logistic regression revealed that the SWE value and end diastolic velocity (EDV) of the interlobar artery were found to be independent risk factors for IFTA. For the diagnosis of IFTA, the area under the ROC curve (AUC) of SWE alone was 0.652, whereas the AUC of SWE in combination with the EDV was 0.807 (p = 0.008). CONCLUSION: The combination of Doppler ultrasound imaging and SWE measurements could improve the diagnostic performance of quantitative assessment of IFTA in IgAN patients.

Silver Nanoclusters-Decorated Porous Microneedles Coupling Duplex-Specific Nuclease-Assisted Signal Amplification for Sampling and Detection of MicroRNA in Interstitial Fluid.

MicroRNAs (miRNAs) in dermal interstitial fluid (ISF) have recently been recognized as clinically promising biomarkers for the diagnosis and prognosis of cancer. However, the detection poses significant challenges, primarily due to the low abundance of miRNAs and the limitations of current sampling techniques. To address this issue, we develop novel porous microneedles (PMNs) array-based sensor composed of poly(vinyl alcohol) porous hydrogel and DNA-templated silver nanoclusters (AgNCs) to facilitate the enrichment and highly sensitive detection of ISF miRNA. Leveraging the capillary action facilitated by its unique porous structure and the swelling properties of the hydrogel, the PMNs array can efficiently extract 2.7 ± 0.3 mg of ISF within 5 min. Additionally, the interconnected pores within the PMNs array contribute to an increased specific surface area, thereby offering a convenient platform for the decoration of DNA-templated AgNCs. The immobilized large amount of AgNCs effectively capture the target miRNA from the extracted ISF, resulting in miRNA-induced fluorescence quenching of AgNCs. Subsequently, the introduction of the duplex-specific nuclease leads to the cleavage of DNA in DNA-RNA heteroduplexes, which release miRNA to interact with other AgNCs. This process of target recycling triggers a further reduction in fluorescence intensity, thereby enabling sensitive detection of the low-abundant miRNA down to 1.6 pM. Both in vitro and in vivo experiments validate the efficacy of the AgNCs immobilized PMNs array for the detection of miRNA biomarkers in ISF within minutes. These results indicate that the proposed PMNs array-based sensor holds great potential for the development of noninvasive personalized diagnostic strategies.

Zanubrutinib ameliorates experimental idiopathic inflammatory myopathy-associated interstitial lung disease by BTK/NF-κB signaling pathway.

Idiopathic inflammatory myopathy, abbreviated as myositis, is a heterogeneous disease characterized by proximal muscle involvement and chronic inflammation, primarily affecting the lungs. The aim of this study was to establish a stable idiopathic inflammatory myopathy (IIM)-associated interstitial lung disease (ILD) mouse model and evaluate the effects of zanubrutinib on IIM-ILD. We induced an IIM lung involvement model in balb/c mice through subcutaneous injection of skeletal muscle homogenate and intraperitoneal injection of pertussis toxin. We observed that the combination of skeletal muscle protein and pertussis toxin in balb/c mice could establish a stable IIM lung involvement model, characterized by muscle inflammation and pulmonary interstitial changes similar to clinical pathology. Zanubrutinib alleviated IIM and ILD, and its anti-inflammatory properties were demonstrated by a reduction in inflammatory cells and inflammatory factors in bronchoalveolar lavage fluid and bronchial inflammation. Its anti-inflammatory and anti-fibrotic effects were mainly achieved through the inhibition of BTK and NF-κB phosphorylation. This study established a stable IIM-ILD animal model and demonstrated for the first time that the BTK inhibitor zanubrutinib effectively attenuates experimental IIM-ILD in this model.

2024 update of the recommendations of the French Society of Rheumatology for the diagnosis and management of patients with rheumatoid arthritis.

The French Society of Rheumatology recommendations for managing rheumatoid arthritis (RA) has been updated by a working group of 21 rheumatology experts, 4 young rheumatologists and 2 patient association representatives on the basis of the 2023 version of the European Alliance of Associations for Rheumatology (EULAR) recommendations and systematic literature reviews. Two additional topics were addressed: people at risk of RA development and RA-related interstitial lung disease (RA-ILD). Four general principles and 19 recommendations were issued. The general principles emphasize the importance of a shared decision between the rheumatologist and patient and the need for comprehensive management, both drug and non-drug, for people with RA or at risk of RA development. In terms of diagnosis, the recommendations stress the importance of clinical arthritis and in its absence, the risk factors for progression to RA. In terms of treatment, the recommendations incorporate recent data on the cardiovascular and neoplastic risk profile of Janus kinase inhibitors. With regard to RA-ILD, the recommendations highlight the importance of clinical screening and the need for high-resolution CT scan in the presence of pulmonary symptoms. RA-ILD management requires collaboration between rheumatologists and pulmonologists. The treatment strategy is based on controlling disease activity with methotrexate or targeted therapies (mainly abatacept or rituximab). The prescription for anti-fibrotic treatment should be discussed with a pulmonologist with expertise in RA-ILD.

Algorithm-based Mobile Texting Platform for the Self-management of Interstitial Cystitis/Bladder Pain Syndrome: Pilot Study Evaluating Feasibility, Usability and Potential Utility.

INTRODUCTION: We developed an algorithm-based mobile texting platform for promoting self-management in patients with interstitial cystitis/bladder pain syndrome (IC/BPS). Our aim was to measure the feasibility, usability, and potential utility of the platform. MATERIAL AND METHODS: A texting platform that delivered four treatment modules (education and behavioral modification, cognitive behavioral therapy, pelvic floor physical therapy, and guided mindfulness practices) and an automated weekly message over six weeks was developed. Feasibility and usability were determined using patient engagement (proportion of platform messages to which patients responded) and System Usability scale. Satisfaction with patient-physician communication questionnaire, Pain Self-Efficacy Scale, and Interstitial Cystitis Symptom and Problem Index were administered before and after the intervention. RESULTS: Engagement with the platform in 52 female patients with IC/BPS [median age (IQR) 40 (30-48) years] was 76.9%. The commonest module selected by patients was pelvic floor physical therapy (50%) followed by cognitive behavioral therapy (34%), and guided mindfulness (15%). System Usability score (median, IQR) was 87 (83-95), indicating high usability. Satisfaction with patient-physician communication improved significantly (median change 4, IQR 1-9, p< .001). Pain self-efficacy score improved from moderate impairment at baseline to minimal impairment at six weeks (median change 10, IQR 2-18, p < .001). Urinary symptoms scores also improved (median change Interstitial Cystitis Symptom Index -3, IQR -5, -1.5, p < .001, Problem Index -2, IQR 5.5, -0.5, p <.001). CONCLUSION: An automated mobile platform has the potential for improving access to self-management strategies and easing clinicians' challenge of counseling IC/BPS patients during time-limited in-person visits.

Emodin repairs interstitial cells of Cajal damaged by cholelithiasis in the gallbladder.

Background: Hypercholesterolemia induces cholelithiasis and dysfunction of gallbladder motility. Interstitial cells of Cajal (ICCs) contribute to gallbladder motility. Emodin modulates the contractility of the gallbladder muscle; however, the underlying mechanism is unknown. Aim: This study aimed to explore the effects of emodin on gallbladder ICCs with cholelithiasis in a guinea pig model. Methods: Animals were randomly divided into a healthy control group and three study groups. All study groups received a high-cholesterol diet (HCD) for 8 weeks. Subsequently, they were randomly assigned to either the HCD group or one of the emodin treatment groups lasting 4 or 8 weeks. Total cholesterol (TC) and triglycerides (TG) were measured to determine changes in serum lipid levels. Immunohistochemistry was performed to detect the morphology and number of ICCs. TUNEL assays were performed to detect ICC apoptosis. Transmission electron microscopy was employed to observe ICC structure. Western blotting and real-time polymerase chain reaction were used to detect changes in stem cell factor (SCF)/c-kit pathway expression. Results: Serum TC and TG were higher in all study groups. In cases of cholelithiasis, the SCF/c-kit pathway was downregulated, the number of gallbladder ICCs decreased, apoptosis increased, and the ICC network structure was damaged. After emodin treatment, the SCF/c-kit pathway was upregulated, the number of gallbladder ICCs increased, apoptosis decreased, and the ICC network structure recovered. Conclusion: Cholelithiasis downregulates the SCF/c-kit pathway and damages gallbladder ICCs. Emodin upregulates the SCF/c-kit pathway and increases gallbladder ICCs, contributing to recovery from gallbladder motility disorders.\.

Favorable Response to Adjuvant Tofacitinib in a Case of Anti-Melanoma Differentiation-Associated Gene-5 Antibody Positive Clinically Amyopathic Dermatomyositis.

Anti-melanoma differentiation-associated gene-5 antibody (anti-MDA-5 Ab) associated with clinically amyopathic dermatomyositis (CADM) is characterized by vasculopathic ulcers, mechanic's hands, and progressive interstitial lung disease (ILD). We present a case of 38-year-old female who presented with all these classical clinical features. Her investigations revealed normal serum muscle enzyme levels and the presence of anti-Mi2 and anti-MDA-5 antibodies by immunoblot. Imaging study revealed changes suggestive of ILD. She was treated with rituximab along with oral glucocorticoid and other supportive treatment to which she didn't respond adequately. Recently, it has been postulated that plasmacytoid dendritic cells produce interferon which is responsible for tissue injury in dermatomyositis (DM). Tofacitinib, by inhibiting JAK-STAT pathway, inhibits downstream cytokines, mainly type 1 interferon. So, we added tofacitinib as adjuvant therapy in our patient. Post-six months of commencement of adjuvant tofacitinib, patient experienced remarkable improvement in cutaneous features as well as in pulmonary fibrosis.

A case report navigating CVID and sarcoidosis overlaps in pediatric nephritis.

Common variable immunodeficiency (CVID) can be complicated by granulomatous disease, often granulomatous lymphocytic interstitial lung disease (GLILD). Granulomatous interstitial nephritis represents an atypical presentation in pediatrics. Our patient is a previously healthy 13-year-old white male with a recent diagnosis of CVID. He presented with a rash and laboratory findings included pancytopenia (white blood cells 2.6 cells × 103/µl, hemoglobin 11.8 g/dl, platelets 60 × 103/µl), hypercalcemia (14.9 mg/dl), elevated Vit D 1,25 OH level (>200 pg/ml), hyperuricemia (8.8 mg/dl), and acute kidney injury (AKI) (serum creatinine 1.1 mg/dl; baseline 0.64 mg/dl). A broad infectious workup was unremarkable. The rash improved with empiric doxycycline. Hypercalcemia and hyperuricemia were managed with fluid resuscitation, calcitonin, and zoledronic acid. Evaluation for malignancy including a positron emission tomography scan, revealed multiple mediastinal hypermetabolic lymph nodes and pulmonary ground glass opacities, later reported as small pulmonary nodules by computed tomography (CT). Splenomegaly was confirmed by ultrasound and CT. Peripheral smear, bone marrow biopsy, and genetic testing were non-revealing. His angiotensin-converting enzyme level was elevated (359 U/L), raising concerns for sarcoidosis. Given Stage 1 AKI, a renal biopsy was pursued and identified non-caseating granulomatous interstitial nephritis. Treatment with 60 mg of prednisone began for presumed sarcoidosis for 4 months, causing steroid-induced hypertension and mood changes. Zoledronic acid minimally reduced serum creatinine. Pneumocystis jirovecii pneumonia prophylaxis was initiated due to T-cell cytopenia. Chest CT findings showed a suboptimal response to steroids. A bronchoalveolar lavage demonstrated >50% lymphocytes (normal <10%) and the lung biopsy exhibited non-caseating granulomas, indicating GLILD. Rubella was identified by staining. Following a fever, he was found to have elevated liver enzymes and confirmed hepatitis with portal hypertension on CT. A liver biopsy revealed epithelioid non-caseating granuloma and HHV6 was detected by PCR. He was treated with four cycles of rituximab and granulocyte-colony stimulating factor for persistent neutropenia. Subsequent treatment with mycophenolate led to the resolution of the granulomatous lesions and cytopenias. The rare complication of granulomatous interstitial nephritis in CVID illustrates the intricate nature of diagnosis. This case underscores the necessity for a holistic view of the patient's clinical and immune phenotype, including distinctive radiological presentations, for precise diagnoses and tailored management of CVID.